Abstract
Despite the high prognostic value of immune infiltrates in colorectal cancer (CRC), metastatic disease remains resistant to immunotherapy by immune checkpoint blockade (ICB). Here, we show, in metastatic CRC preclinical models, that orthotopically implanted primary colon tumors exert a colon-specific antimetastatic effect on distant hepatic lesions. Enterotropic α4β7 integrin-expressing neoantigen-specific CD8 T cells were key components of the antimetastatic effect. Accordingly, the presence of concomitant colon tumors improved control of liver lesions by anti-PD-L1 proof-of-concept immunotherapy and generated protective immune memory, whereas partial depletion of α4β7+ cells abrogated control of metastases. Last, in patients with metastatic CRC, response to ICB was associated with expression of α4β7 integrin in metastases and with circulating α4β7+ CD8 T cells. Our findings identify a systemic cancer immunosurveillance role for gut-primed tumor-specific α4β7+ CD8 T cells.